Increasing transplant mass results in long-term allograft survival and recovery from transplant vasculopathy

Late allograft rejection due to transplant vasculopathy continues to be a major clinical problem. Increasing the ratio of donor transplant size to recipient weight has been shown to reduce the incidence of late allograft failure. Using a murine pancreas transplant model we have tested the hypothesis that increasing the donor transplant size in a recipient can promote long-term allograft survival by promoting recovery from transplant vasculopathy. Recipients of an allograft that showed extensive vasculopathy were transplanted with a second donor transplant. The effect of the second allograft on the vasculopathy present in the first graft was measured. Transplanting a second allograft reversed all signs of ongoing rejection, including transplant vasculopathy, resulting in long-term survival of the first graft. Vasculopathy was only reversed if the first and second grafts were from the same mouse strain, suggesting an antigen-specific mechanism. However, the recovery of the first graft was not associated with antigen-specific peripheral tolerance.     

Fluorescence in situ hybridization investigation of cutaneous lesions in acute promyelocytic leukemia.

Cutaneous manifestations of acute promyelocytic leukemia are rare but well documented. Skin biopsies of leukemia can be difficult to confirm using morphology alone, and paraffin section immunophenotyping is not specific in separating acute promyelocytic leukemia from other acute myeloid leukemias involving the skin or inflammatory conditions, such as Sweet's syndrome and all-trans retinoic acid-associated genital ulcers, which may mimic leukemia cutis. Fluorescence in situ hybridization has been shown to be a fast and effective method of detecting the PML/RARA fusion gene characteristic of acute promyelocytic leukemia in fresh blood and bone marrow samples. Fluorescence in situ hybridization has also been demonstrated to be effective in detecting other chromosomal rearrangements in paraffin-embedded tissue. This retrospective study of cutaneous lesions from four patients with acute promyelocytic leukemia evaluates the utility of performing fluorescence in situ hybridization to confirm the presence of cutaneous manifestations of acute promyelocytic leukemia in formalin-fixed, paraffin-embedded skin biopsies. All patients had previous bone marrow findings of acute promyelocytic leukemia with characteristic morphology, immunophenotype, and cytogenetic studies, which detailed the presence of the t(15;17)(q22;q12) rearrangement. Two skin biopsies showed an infiltrate of blastic cells involving the dermis in a diffuse pattern and one biopsy had a perivascular/periadnexal pattern. The fourth case, involving the scrotum, showed a predominant neutrophilic infiltrate diffusely involving the dermis and epidermis with a subset of blastic cells. Nuclei were extracted from core biopsies of the formalin-fixed paraffin-embedded tissue and fluorescence in situ hybridization was performed using a dual color, dual fusion PML / RARA probe. All cases showed evidence of the t(15;17) rearrangement, with 90, 79, 51 and 16% positive signal patterns, each well above background limits. Fluorescence in situ hybridization appears to be a robust technique to detect cutaneous manifestations of acute promyelocytic leukemia in formalin-fixed paraffin-embedded skin biopsies.     

Oligomerization and polymerization of the filovirus matrix protein VP40

The matrix protein VP40 from Ebola virus plays an important role in the assembly process of virus particles by interacting with cellular factors, cellular membranes, and the ribonuclearprotein particle complex. Here we show that the N-terminal domain of VP40 folds into a mixture of two different oligomeric states in vitro, namely hexameric and octameric ringlike structures, as detected by gel filtration chromatography, chemical cross-linking, and electron microscopy. Octamer formation depends largely on the interaction with nucleic acids, which in turn confers in vitro SDS resistance. Refolding experiments with a nucleic acid free N-terminal domain preparation reveal a mostly dimeric form of VP40, which is transformed into an SDS resistant octamer upon incubation with E. coli nucleic acids. In addition, we demonstrate that the N-terminal domain of Marburg virus VP40 also folds into ringlike structures, similar to Ebola virus VP40. Interestingly, Marburg virus VP40 rings reveal a high tendency to polymerize into rods composed of stacked rings. These results may suggest distinct roles for different oligomeric forms of VP40 in the filovirus life cycle.     

Leukocyte-reduced transfusions in cardiac surgery results of an implementation trial

An implementation trial of leukocyte-reduced transfusions in cardiac surgery (primary coronary artery bypass graft and valve replacement) was performed from July to December 1998; comparisons were made with data from the same period in 1997. Patients from both periods were similar in important preoperative and intraoperative variables (age, sex, weight, number of units of RBCs transfused, ejection fraction). The mean total number of complications was statistically significantly decreasedfrom 0.26 complications per patient in the non-leukocyte-reduced to 0.19 in the leukocyte-reduced recipients. Overall, the mean +/- ISD costs of care per patient decreasedfrom 1997 ($27,615 +/- $33,973) to 1998 ($27,038 +/- $24,107). Mean costs decreased $1,700 per patient for recipients of leukocyte-reduced blood in 1998 compared with recipients of non-leukocyte-reduced blood in 1997 Mean costs increased $4,000 per patient in patients who did not receive transfusions in 1998 compared with 1997. Hospitalization costs decreased when leukocyte-reduced transfusions were implemented for patients undergoing cardiac surgery in our institution. Implementation of leukocyte reduction may be cost neutral or cost saving in at least some settings.     

Infestation of sand lizards (<Emphasis Type="Italic">Lacerta agilis</Emphasis>) resident in the Northeastern Poland by <Emphasis Type="Italic">Ixodes ricinus</Emphasis> (L.) ticks and their infection with <Emphasis Type="Italic">Borrelia burgdorferi</Emphasis> sensu lato

Sand lizards (Lacerta agilis) were trapped and examined for ticks from May to September in 2002 and 2003 in Northeastern Poland. A total of 233 Ixodes ricinus (L.) ticks (76 larvae and 157 nymphs) was found on 31 of 235 captured lizards (13.2%). The tick infestation is relatively low compared to that of mammals and passerine birds from the same area (Siński et al. 2006, Gryczyńska et al. 2002). Tick infestation depended on the month of capture, being the highest in spring. In autumn no ticks were recorded on any of the captured lizards. The oldest lizards carried the highest number of ticks but no differences related to sex of the host were found. All the collected ticks were analysed by PCR for the presence of Borrelia burgdorferi sensu lato, the etiological agents of Lyme disease. Spirochetes were detected in 11 out of 233 (4.7%) ticks tested. Genetic analysis confirmed that the spirochetes are members of the Borrelia afzelii, B. garinii and B. burgdorferi sensu stricto genospecies. Mixed infection were not detected. The prevalence of infection was analysed in relation to months of the capture, age and sex of the lizards, but differences were not statistically significant. The obtained results suggest that lizards are probably not B. burgdorferi reservoirs, but further studies are required to confirm this.     

The NAD(P)H:quinone oxidoreductase I C609T polymorphism modifies the risk of Barrett esophagus and esophageal adenocarcinoma.

PURPOSE: The role of genetic susceptibility to esophageal adenocarcinoma and its precursor lesion Barrett esophagus has not been fully elucidated. This study investigated the effect of polymorphisms in the manganese superoxide dismutase (MnSOD) and NAD(P)H:quinone oxidoreductase 1 (NQO1) genes in modulating the risk of developing Barrett esophagus or esophageal adenocarcinoma. METHODS: A total of 584 patients (146 esophagitis, 200 Barrett esophagus, 144 esophageal adenocarcinoma, and 94 controls) were genotyped for the MnSOD C14T and NQO1 C609T polymorphisms using polymerase chain reaction and restriction fragment length polymorphism analysis. RESULTS: The NQO1 TT genotype was less common in Barrett esophagus (2.0%) and esophageal adenocarcinoma (1.4%) patients, compared with both esophagitis patients (7.6%) and controls (5.4%). After adjustment for sex, age, body mass index, reflux symptoms, and smoking status, patients with the homozygous TT genotype had a 4.5-fold decreased risk of developing Barrett esophagus (odds ratio = 0.22, 95% confidence interval = 0.07-0.76, P = 0.01) and a 6.2-fold decreased risk of esophageal adenocarcinoma (odds ratio = 0.16, 95% confidence intervals = 0.03-0.94, P = 0.04) compared with individuals with the TC and CC genotypes. No significant differences between groups were observed for the MnSOD polymorphism (P = 0.289). CONCLUSIONS: Overall, the results of this study suggest that the NQO1 TT genotype may offer protection from reflux complications such as Barrett esophagus and esophageal adenocarcinoma.     

Development of oculomotor functioning in preadolescence, adolescence, and adulthood

We examined developmental differences in smooth pursuit eye tracking proficiency in a large sample of preadolescent, adolescent, and adult males. Smooth pursuit was quantified using general measures of oculomotor functioning and by examining the frequency and dynamic characteristics of specific saccadic events. Examination of age effects using general measures indicated that, by late adolescence, the smooth pursuit system reached adult levels of functioning. No significant differences were found between the adolescent and adult groups on most global measures. However, both groups had better eye tracking than the preadolescent group, suggesting that during preadolescence the oculomotor system is still developing and is not yet capable of optimal performance. Examination of the frequency and dynamic characteristics of the saccadic events yielded additional information regarding the nature of the smooth pursuit eye tracking differences of the three age groups.     

Checkpoint Blockade Immunotherapy Induces Dynamic Changes in PD-1−CD8+ Tumor-Infiltrating T Cells

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Evidence for linkage of nonsyndromic cleft lip with or without cleft palate to a region on chromosome 2

Results from a genome-wide screen of 10 multiplex families ascertained through probands with nonsyndromic cleft lip with or without cleft palate (CL/P) in Mexico, Argentina, and the United States yielded suggestive evidence of linkage to chromosomes 2, 6, 17 and 18. Fine mapping excluded all regions except chromosome 2. Subsequent analysis was performed on the original 10 families plus an additional 16 families using 31 markers on chromosome 2. This analysis showed intriguing evidence of linkage to 2q (Zlr=2.26, empirical P-value=0.028 in a chromosome-wide analysis). Transmission disequilibrium tests also revealed evidence of linkage and disequilibrium for two markers in this region (D2S168 and D2S1400 with P-values=0.022 and 0.006, respectively). A subset of these 26 families provided additional evidence for a susceptibility gene for CL/P on 2q, suggesting that further studies of genes in this region are warranted.